"Context-sensitive half-time"
Of the main pharmacokinetic variables, half-life is the easiest to comprehend. However
it gives little information about the bahaviour of a drug in a single compartment, and
cannot predict the behaviour of drugs with two or three compartment models. A more
useful descriptor, "context-sensitive half-time" is where the
"context" refers to the duration of infusion and the "half-time" is
the time required for the drug concentration in the central compartment to decline by half
after infusion is stoped. The concept can be extended from a 50% decrease to an 80%
decrease, which is more closely related to the offset of action.

The differance between single injection and prolonged infusion arises when distribution
from the central to the peripheral comparments is responsible for a considerable part of
the offset of action of a drug

Other opioid agonists

Tramadol

Mode of action:

Weak mu opioid receptor agonist

Metabolised by CYP2D6 to
ortho-desmethyltramadol, which is a reasonable mu opioid receptor agonist

Inhibition of noradrenaline uptake

Release of serotonin

Biokinetics

Rapidly absorbed with an initial bioavailability of 68% after a single dose

Appears in plasma in 15-45 minutes with a peak concentration at 2-4 hours

High tissue affinity with a volume of distribution 200-300 litres

20% protein binding

Liver metabolism by CYP2D6 to
ortho-desmethyltramadol with subsequent sulphation or glucuronidation

Post-operative mortality is a rare occurrence in healthy patients undergoing short,
minor surgical procedures. It is unreasonable to expect a reduction in mortality and so
should not be used as a rationale for centroneuraxis opioids in this patient population.
Post-operative mortality in high risk patients undergoing major surgery is reduced by the
usage of centroneuraxis opioids, in the post-operative period. The exact mechanism
underlying this phenomenon is still unknown, we do know that post-operative pain
contributes to the "stress response" which is a plethora of hormonal changes
following surgery. The sympathetic nervous system is activated in this "stress
response" increasing circulating catecholamine concentrations. Catecholamines
stimulate the cardiovascular system and enhance platelet activation, which may play an
important role in the incidence, timing and severity of myocardial ischaemia in patients
with coronary artery disease. Epidural opioids are superior in decreasing the circulating
catecholamine concentrations, and the resultant hypercoagulable state in the
post-operative period. Exactly which group of patients will definitely benefit from
centroneuraxis opioids, the level and duration of pain relief necessary and whether or not
the addition of local anaesthetics contributes to a further decreases in the "stress
response", or in fact if it is the reduction in the hormonal "stress
response", that is crucial to the improved outcome, has all still to be decided

Dose sparing effectMorphine is the only opioid which shows a dose sparing effect by
epidural and intrathecal placement. 1/4 of the parentral dose (0.1-0.2mg/kg) is effective
epidurally (0.02-0.05mg/kg) and 1/100 of the parentral dose is effective intrathecally
(0.001-0.005mg/kg). Although meperidine (pethidine) has both local anaesthetic and opioid
properties 7/10 of the parentral dose (1-2mg/kg) is needed epidurally (.7-1mg/kg) and in
an equivalent dose intrathecally (1mg/kg). No other opioids display any dose sparing
effect. Fentanyl, butorphanol and alfentanil all require 100% of the parentral dose when
given epidurally or intrathecally. Sufentanil actually requires a larger intrathecal and
epidural than parentral dose. The theoretical explanations of this phenomenon are:Dural
permeability was thought to increase with increasing lipid solubility. Drugs have to
pass through lipid and water barriers to traverse the dura and arachnoid membranes,
eventually the advantage of increasing lipid solubility is lost by slow transfer through
hydrophilic regions. This theory fails to explain why there is no advantage to intrathecal
administration which bypasses the dural membrane.Non-specific binding analogous to
the blood gas partition coefficient of inhalational agents. Lipid soluble opioids diffuse
extensively into epidural fat and the spinal cord white matter, leaving relatively little
drug to reach the spinal opioid receptors in the grey matter.Synergy between
supraspinal and spinal opioid action is the most elegant theory. All opioids are rapidly
absorbed into the circulation after epidural injection and have access to supraspinal
sites of action. Morphine acts at all opioid receptors resulting in a synergy between the
supraspinal and the spinal effects. Fentanyl and sufentanil have increasing specificity
for the m receptor subtypes and may lack a synergistic interaction between
supraspinal and spinal action.

Decreased opioid side effects

Morphine centroneuraxis blockade decreases sedation, but increases pruritis, which is
associated with herpes reactivation, urinary retention and nausea compared to systemic
administration. Fentanyl and sufentanil require centroneuraxis dosages identical or
greater than parentral doses, the plasma drug concentration are similar and so the
incidence and severity of side effects are comparable. Treatment of these side effects
with continuous infusion of naloxone at 2-5mg/kg/hour does not
appear to reduce the analgesia of centroneuraxis morphine, as it would for parentral
morphine. Oral administration of the long-acting antagonist naltrexone 3-6mg may diminish
analgesia. The partial agonists nalbuphine (5-10mg ivi) and butorphanol (1-2mg ivi)
effectively reverses the side effects without affecting the analgesia. Purely symptomatic
treatment with droperidol (0.5-1mg ivi) for the nausea and diphenhyramine.(12.5-25mg ivi)
for the pruritis is also effective.

Centroneuraxis opioids reduces the risk of respiratory depression

Dermatomal level of analgesia ascends slowly after epidural morphine injection,
reaching the cervical levels 6-8 hours after injection. This corresponds to the time for
circulation of morphine in the cerebrospinal fluid and accounts for the delayed
respiratory depression seen when high morphine concentrations are achieved in the
cerebrospinal fluid bathing the respiratory centres in the brainstem. As anaesthetics we
expect and indeed observe rapid, extensive dermatomal spread after lumbar intrathecal
injection of isobaric bupivacaine but anticipated a restricted spread of fentanyl which is
not much more lipid soluble than bupivacaine. The odd observation is not the rapid
cephalad spread of fentanyl, but the slow cephalad spread of morphine. This rapid cephalad
spread of lipid soluble opioids may explain the rapid onset of severe respiratory
depression following centroneuraxis administration. The relatively large doses of lipid
soluble opioids that must be employed in centroneuraxis blockade, may result in delayed
respiratory depression following systemic absorption. We must not use a decrease in
respiratory depression as a rationale for using centroneuraxis opioids.Morphine is the
opioid of choice for epidural usage. A single injection yields 12 to 24 hours of
analgesia, which covers the patient for the most painful post operative period. Continuous
infusion of 0.2-0.6mg/hour can prolong analgesia provided there is a high awareness of
pump malfunction or misprogramming and catheter migration into a blood vessels, which
would result in loss of analgesia. Patient controlled analgesia with epidural morphine can
also be successfully utilised.Morphine is the opioid of choice for intrathecal usage
following the withdrawal of spinal catheters, it is the only drug that can provide 12 to
24 hours of pain relief following a single intrathecal injection.Pethidine can be used to
good effect intrathecally providing 8-12 hours of pain relief following a single
intrathecal injection.